Timothy Syndrome

NORD gratefully acknowledges Katherine W. Timothy of Children's Hospital, Harvard Medical School, for assistance in the preparation of this report.

General Discussion

Timothy syndrome (TS) is a rare genetic disorder characterized by a spectrum of problems that include an abnormally prolonged cardiac "repolarization" time (long QT interval). This refers to the process of returning heart cells to a resting state in preparation for the next heartbeat. The prolonged repolarization time predisposes individuals to abnormal heart rhythms (arrhythmias), cardiac arrest and sudden death. Other problems included in the TS spectrum are webbing of fingers and/or toes (syndactyly); structural heart abnormalities present at birth (congenital); a weakened immune system; developmental delays and autism. Timothy syndrome was identified in 2004 by researchers at Children's Hospital Boston, Howard Hughes Medical Institute, University of Utah and University of Pavia, Pavia, Italy.

Despite the complexity of health concerns, this syndrome arises from a single, spontaneous mutation in the Ca(v)1.2 Calcium Channel gene called CACNA1C. Multiple body systems are affected by this mutation due to impairment of a very fundamental cell ion channel, found in most tissues and organs, which controls the amount of calcium entering a cell. As a result of this mutation, the ion channel gating closure is affected and cells are overwhelmed by a continuous influx of calcium. The affected gene is active (expressed) in cardiac muscle cells as well as tissues of the gastrointestinal system, lungs, immune system, smooth muscle, testes, and brain, including regions of the brain that are associated with abnormalities observed in autism.

All affected children studied presented at birth with severe prolongation of time for heart muscle to expand and contract (depolarization and repolarization of cardiac tissue as measured by the QT interval) on their electrocardiograms (ECG). Life-threatening periods of disturbed heart rhythms in many cases were associated with anesthesia during surgeries, infections and severe illnesses (pneumonia). All children were born with webbed fingers and/or toes.

Most children diagnosed with Timothy syndrome were born with malformations of the heart. These included developmental abnormalities wherein holes in the walls between chambers of the heart failed to close (ASD, VSD, PDA, and PFO) and other malformations such as the combination of heart defects known as tetralogy of Fallot.

Several of the surviving children were identified as having a type of autism or one of the autism spectrum disorders. However, the relationship between Timothy syndrome and autism is not yet well understood.

Causes

Recent studies show that Timothy syndrome is the result of a spontaneous change (mutation) in the CACNA1C gene located on the short arm of chromosome 12 (12p13.3). This gene controls the production of the protein that directs the manufacturing of calcium ion channels within the cell wall of most cells. These channels have gates that open and close, specifically allowing calcium ions to pass in and out of the cells. The TS mutation specifically inhibits the gates from closing properly, causing the cells to become overwhelmed with a continuous influx of calcium.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbred from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. For example, chromosome 12p13.3 refers to band 13.3 on the short arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Affected Populations

The identification of Timothy syndrome was accomplished by researchers from several institutions including Children’s Hospital Boston, Howard Hughes Medical Institute, University of Utah and Pavia University, Pavia, Italy. The TS disorder was named for a member of this research team, Katherine W. Timothy of the University of Utah.

During 12 years of the studies, 17 children were identified with this disorder, seven of whom were living at the time the research was first published in October 2004. Those known to be affected by TS included both males and females. The average age at death in TS children was 2.5 years (females appearing to have a greater survival rate than males), with the oldest living TS individual presently known being 20 years of age.

Related Disorders

Only the relationship of QT interval prolongation in the following disorders is similar to those of Timothy syndrome; however, comparisons may be useful for a differential diagnosis.

Jervell and Lange-Nielsen syndrome (JLNS), also known as cardioauditory syndrome, is a rare disorder characterized by sensorineural deafness at birth, fainting spells (syncope), and prolonged QT interval repolarization of electrical activity in the ventricles of the heart, which can cause apparent seizures and a fast, uneven heartbeat (ventricular fibrillation). Affected individuals may experience episodes of unconsciousness, cardiac arrest and, potentially, sudden death. Physical activity, excitement or stress generally triggers the onset of these symptoms. JLNS is usually detected during early childhood as a result of evaluation for frequent fainting spells. Although the associated deafness in JLNS is inherited as an autosomal recessive trait, the prolonged QT interval characteristic is inherited as an autosomal dominant trait and as such, when JLNS is suspected, all other family members should also be evaluated for the long QT syndrome. (Although many young TS children may appear deaf, as observed by their general lack of response to auditory commands, when evaluated, deafness is not identified. The lack of auditory response in TS children is probably a result of faulty brain processing as recognized in autistic spectral disorders.) (For more information on this disorder, choose “Jervell and Lange-Nielsen syndrome” as your search term in the Rare Disease Database.)

Acquired long QT syndrome is a rare heart disorder characterized by heart rhythm abnormalities potentially resulting in the loss of consciousness, cardiac arrest, and sudden death. This disorder most often occurs after the administration of certain medications. Some researchers believe affected individuals may be genetically susceptible to the development of acquired long QT syndrome. Neurological disorders, strokes, and electrolyte imbalances have also been indicated as potential causes of acquired long QT syndrome.

Romano-Ward syndrome, also referred to as long QT syndrome, is an inherited cardiac disorder characterized by abnormalities affecting the electrical system of the heart. The severity of Romano-Ward syndrome varies greatly from case to case. Some individuals have no apparent symptoms (asymptomatic); others may develop abnormally increased heartbeats (tachyarrhythmias) resulting in episodes of unconsciousness, cardiac arrest, and, potentially, sudden death. Romano-Ward syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Romano-Ward syndrome” as your search term in the Rare Disease Database.)

Diagnosis

The combination of webbed fingers and/or toes, congenital cardiac abnormalities and a markedly prolonged QT interval is diagnostic of the TS disorder. Other facial anomalies such as a flat nose bridge, low set ears, thin upper lip, protruding lower jaw can also give additional weight to the diagnosis.

Standard Therapies

Treatment

Beta-blocker medications are generally used to treat patients with irregular heartbeats and prolonged QT intervals; however, whether this would be the drug of choice in TS patients remains in question. Pacemakers are often placed to pace infants and children at faster heart rates for improved cardiac function. Internal or external defibrillators are also considered prudent but internally placed defibrillators also put the TS child at increased risk for problems associated with anesthesia and device site infections.

Investigational Therapies

Because Timothy syndrome is associated with an uncontrolled influx of calcium as a result of the calcium channel malfunction, it is possible the syndrome may be treatable with calcium channel-blocking drugs as has been suggested as beneficial in animal studies. Additional research will be needed to verify this possibility.

Research on Timothy syndrome, its causes and possible treatments may also add to the body of knowledge about autism and the autism spectrum of diseases.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact

Years Published

2005

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